How ascending sensory information is integrated in the neocortex has been extensively studied in the last several decades. This sustained interest in cortical sensory integration stems from the belief that sensory processing underlies key aspects of cognitive functions and dysfunctions, such as sensory perception, sensory discrimination, trauma and other cognitive dysfunctions. In sensory cortices, layer 4 constitutes the main target layer for specific thalamocortical afferents and is the layer in which cortical sensory processing begins. It is known that only approximately 5-15% of excitatory synapses onto layer 4 neurons are from thalamocortical (TC) fibers, whereas the majority of other excitatory synapses are from intracortical (IC) fibers. However, the relative importance of TC and IC connections to sensory processing is still in debate, due in part to the poor understanding of the cellular and molecular properties of these connections. Some studies have suggested that TC synapses are strong and reliable enough to convey sensory information into the cortex, while others have argued that recurrent IC synapses are indispensable in amplifying and dynamically regulating TC inputs, hi addition, how synaptic strengths of TC and IC connections are maintained and regulated is unclear. Combining electrophysiology, molecular biology and genetics techniques, we have recently found that synaptic responses at IC and TC synapses display different kinetics, which may represent a novel and important strategy for integrating and amplifying sensory inputs. Our preliminary data also suggest that the differences of kinetics at these synapses are due to synapse-specific delivery of distinct AMPA-sensitive glutamate receptors (-Rs). Based on these results, I hypothesize that postsynaptic regulation of transmission is synapse-specific in layer 4 cortical neurons. We will examine what controls the synaptic kinetics and efficacy of transmission at IC synapses. Moreover, we will determine what regulates synaptic kinetics and efficacy of transmission at TC synapses. Finally, we will investigate how IC and TC synapses maintain synaptic strength. Because different AMPA-Rs exhibit distinct properties in mediating synaptic transmission and in controlling synaptic efficacy, the results from this project should aid the understanding of sensory physiology of neocortex and cortical pathologies.